Neutrophils are present in a wide variety of inflammatory lesions seen in human disease and have been shown to be necessary for the pathogenesis of tissue damage in experimental models of inflammation. Responses of neutrophils are believed to function in the mediation of inflammatory tissue damage by these cells. A number of these responses can be demonstrated in vitro. When neutrophils are exposed to appropriate stimuli, lysosomal enzymes capable of damaging tissue components are released extracellularly. Enhanced oxidation via the pentose cycle is triggered by H2O2 produced by stimulated cells. Also associated with enhanced glucose oxidation is the production of superoxide (O2-) and hydroxyl (OH.) radicals H2O2, O2-, and OH. are reactive oxidants capable of producing alterations in cells as well as extracellular constituents. We have observed that during phagocytosis and lysosomal enzyme release, there is a significant fall in the ATP level of neutrophils. Prostaglandins and other products of arachidonic acid metabolism are released and may promote or modify the inflammatory process. Lysosomal enzyme release is suppressed by increased cell levels of cyclic AMP and enhanced by cyclic GMP. We have observed that the release of lysosomal enzymes from neutrophils phagocytizing zymosan is dependent on the oxygen tension under which the cells are incubated--with increasing oxygen tension the extent, but not the initial rate, of enzyme release is decreased. Our interpretation of these findings is that a product dependent upon oxidative metabolism generated during the early phase of stimulation of neutrophils exerts a negative feedback influence on lysosomal enzyme release. Possible products capable of this proposed effect include the oxidants cited above, cyclic AMP, and a prostaglandin or other product of arachidonic acid metabolism. One goal of the proposed studies is to identify the factor or factors responsible for the observed effect and to initiate studies on the characterization of its (their) mechanism(s) of action. The second major goal of these studies is to determine the cause and the significance of the fall in ATP which we have observed in cells undergoing phagocytosis and lysosomal enzyme release.